Autoantigen-Induced Focusing of Vβ13+ T Cells Precedes Onset of Autoimmune Diabetes in the LEW.1WR1 Rat
- 1Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA
- 2Division of Endocrinology & Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
- Corresponding author: Elizabeth P. Blankenhorn, .
The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-Vβ13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of Vβ13+ T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of Vβ13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and Wistar Furth) strains induced with polyinosinic:polycytidylic acid. Vβ13+ T cells displayed antigenic focusing in LEW.1WR1 islets 5 days postinduction and were characterized by a substantial decrease in complementarity determining region 3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (days 10–14). Vβ13+ transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-Vα5, an ortholog of the dominant TCR-Vα chain found on insulin B:9-23–reactive T cells in nonobese diabetic rat islets. We observed clonal expansion of Vα5+ transcripts in prediabetic LEW.1WR1 islets, suggesting that rat Vα5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0462/-/DC1.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
- Received March 20, 2013.
- Accepted October 17, 2013.
- © 2014 by the American Diabetes Association.
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